Increased O-GlcNAcylation of c-Myc Promotes Pre-B Cell Proliferation

Abstract

O-linked β-N-acetylglucosamine (O-GlcNAc) modification regulates the activity of hundreds of nucleocytoplasmic proteins involved in a wide variety of cellular processes, such as gene expression, signaling, and cell growth; however, the mechanism underlying the regulation of B cell development and function by O-GlcNAcylation remains largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affected the growth of pre-B cells, which rapidly proliferate to allow expansion of functional clones that express successfully rearranged heavy chains at the pro-B stage during early B cell development. In our study, the overall O-GlcNAc levels in these proliferative pre-B cells, which are linked to the glucose uptake rate, were highly induced when compared with those in pro-B cells. Thus, pharmacologically, genetically, or nutritionally, inhibition of O-GlcNAcylation in pre-B cells markedly downregulated c-Myc expression, resulting in cell cycle arrest via blockade of cyclin expression. Importantly, the population of B cells after the pro-B cell stage in mouse bone marrow was severely impaired by the administration of an O-GlcNAc inhibitor. These results strongly suggest that O-GlcNAcylation-dependent expression of c-Myc represents a new regulatory component of pre-B cell proliferation, as well as a potential therapeutic target for the treatment of pre-B cell-derived leukemia.

O-GlcNAcylation and its role in the immune system

“…Inhibition of O-GlcNAcylation by administration of OGT inhibitors downregulates the expression of c-Myc, cyclin A and cyclin E in a PD36 pre-B cell line. These results suggest that O-GlcNAcylation induces pre-B cells proliferation by increasing the expression of c-Myc and c-Myc downstream genes, such as cyclin A and cyclin E [151].…”

“…Progenitor B cells undergo pro-B, early pre-B and late pre-B stages to become immature B cells in bone marrow. A recent study indicated that O-GlcNAcylation is increased in large pre-B cells and required for the proliferation of pre-B cells [151]. Inhibition of O-GlcNAcylation by administration of OGT inhibitors downregulates the expression of c-Myc, cyclin A and cyclin E in a PD36 pre-B cell line.…”

A portable and high-sensitivity optical sensing system for detecting fluorescently labeled enterohaemorrhagic Escherichia coli Shiga toxin 2B-subunit

“…The collected voltage data were averaged and displayed on the LCD panel on the MCU board. In addition, to determine the availability of live cells for Shiga toxin detection, we performed tests on Gb3-expressing THP-1 and PD36 cells [22] (or parental cells not expressing Gb3, as negative controls) using poly-lysine. All measurements were repeated three times.…”

“…Before stimulation, cells were incubated with RPMI-1640 containing only 10% fetal bovine serum. PD36 cells [22] were cultured in RPMI-1640 containing 10% fetal bovine serum, antibiotic-antimycotic, 0.1 mM MEM nonessential amino acids, 1 mM MEM sodium pyruvate, 55 μM 2-mercaptoethanol, and 2 mM L-glutamine. All cell culture was performed at 37˚C and 5% CO2 in a humidified incubator.…”

Apoptosis and Cell Proliferation Markers in Inflammatory-Fibroproliferative Diseases of the Vessel Wall (Review)

“…Pro-oncogenic c-Myc controls cell proliferation, apoptosis, tissue remodeling, angiogenesis, cell metabolism, and the production of inflammatory and anti-inflammatory cytokines [16][17][18][19][20][21]. Steger et al [22] showed that the use of an antisense oligonucleotide against c-Myc in a mouse venous graft model involves a significant reduction in neointima formation in the postoperative period.…”